Pathophysiology of Transgenic Mouse Models of Huntington's Disease

描述（由申请人提供）：亨廷顿氏病（HD）的致命突变是亨廷顿蛋白中的扩展三核苷酸（CAG）重复，最终导致选择性神经变性，特别是纹状体和皮层。本研究旨在探讨HD患者功能改变的细胞机制。新出现的证据表明，纹状体和皮层神经元和回路的功能障碍发生在疾病表型的发展过程中，远远早于显著的细胞损失。纹状体的形态变化可能最初是由纹状体中等大小的棘神经元（mssn）的内在功能特性的改变引起的，但最终需要皮质纹状体谷氨酸能输入的异常才能表达这种表型。皮质纹状体通路的功能障碍是复杂的，并且存在多种变化，这可以通过与疾病状态显著的年龄相关的短暂和更慢性的相互作用来证明。也有越来越多的证据表明，皮质微回路的变化相互作用，诱导皮质纹状体通路功能障碍。对纹状体和皮层中细胞和电路改变的时间序列以及选择性神经元易感性的原因知之甚少。我们将使用转基因小鼠来解决这些重要的问题。这一建议将研究功能相互作用，使特定的神经元群体更容易受到HD的功能障碍和随后的变性的影响。我们假设，导致HD功能障碍和病理的最明显的细胞改变是细胞间相互作用的结果，而不仅仅是细胞自主变化的结果。我们将在三个具体目标中检验我们的假设，旨在：1。确定HD小鼠模型中纹状体投射神经元亚群和中间神经元易受功能障碍和变性影响的电生理特性2。检查HD小鼠模型大脑皮层兴奋和抑制平衡的变化，这种变化促进和导致纹状体和3的异常。检查是否广泛表达突变亨廷顿蛋白是必要的，以产生不同的电生理改变在已确定的mssn群体。这些研究将为HD的合理治疗提供新的基础，并为进一步了解其他CAG三重重复疾病和神经退行性疾病提供依据。

DESCRIPTION (provided by applicant): The lethal mutation in Huntington's disease (HD) is an expanded trinucleotide (CAG) repeat within the huntingtin protein which ultimately causes selective neurodegeneration especially within the striatum and cortex. This proposal examines cellular mechanisms underlying functional alterations in HD. Emerging evidence indicates that dysfunctions of striatal and cortical neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium- sized spiny neurons (MSSNs), but ultimately require abnormalities in the corticostriatal glutamatergic inputs for the phenotype to be expressed. Malfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. Little is known about the temporal sequence of cellular and circuit alterations, as well as the causes of selective neuronal vulnerability in striatum and cortex. We will use genetically-modified mice to address these important questions. This proposal will examine the functional interactions that occur to make specific neuronal populations more vulnerable to dysfunction and subsequent degeneration in HD. We hypothesize that the most conspicuous cellular alterations leading to dysfunction and pathology in HD result from a combination of cell-cell interactions and are not solely the outcome of cell- autonomous changes. We will test our hypothesis in three specific aims designed to: 1. Determine the electrophysiological properties that make subpopulations of striatal projection neurons and interneurons differentially vulnerable to dysfunction and degeneration in mouse models of HD, 2. Examine the alterations in the balance of excitation and inhibition in the cerebral cortex of mouse models of HD that facilitate and enable abnormalities in the striatum and 3. Examine if widespread expression of mutant huntingtin is necessary to produce differential electrophysiological alterations in identified populations of MSSNs. These studies will provide the basis for novel rational treatments of HD by delineating more restricted targets for drug intervention and also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.